Project Summary The mechanism of Alzheimer's disease (AD) pathogenesis and progression remains unclear. The accumulating evidence points to a major role of cerebrovascular dysfunction in AD. A new insight into how vascular defects or micro-injuries affect AD may open a new avenue for therapeutic intervention. The vascular defects in AD are characterized by pericyte loss and blood-brain-barrier (BBB) breakdown leading to the leakage of plasma components into the brain parenchyma damaging the neurons. Our studies funded by the parent R01 have shown a crucial role of small GTPase R-Ras in regulating the vessel wall integrity in pathologically remodeling vessels. R-Ras is abundantly expressed in endothelial cells (ECs) and pericytes of the normal brain microvasculature. However, we found a substantial downregulation of R-Ras in microvascular ECs and pericytes in AD patents' frontal lobe and hippocampus as well as the transgenic mouse brains exhibiting AD-like amyloidopathy. We hypothesize that R-Ras is protective against AD through protecting cerebral microvessels and BBB integrity. Here, we will test this hypothesis using cell type-specific genetic models of vascular defects and amyloidopathy. We will examine whether R-Ras loss-of-function accelerates and gain-of-function delays the onset and progression of AD-like neurodegeneration in APPSwInd mice. This exploratory study will generate the first evidence for cerebrovascular/neuroprotective role of R-Ras and its significance in AD. Since our experimental design focuses on examining the precise contribution of the vascular involvement in AD, this study provides an opportunity to evaluate the vascular hypothesis of AD and its implication for how to intervene the development of this disease.